A metabolite of daidzein, 6,7,4′-trihydroxyisoflavone, suppresses adipogenesis in 3T3-L1 preadipocytes via ATP-competitive inhibition of PI3K

Scope: Daidzein is one of the major soy isoflavones. Following ingestion, daidzein is readily metabolized in the liver and converted into hydroxylated metabolites. One such metabolite is 6,7,4′-trihydroxyisoflavone (6,7,4′-THIF), which has been the focus of recent studies due to its various health benefits, however, its anti-adipogenic activity has not been investigated. Our objective was to determine the effects of 6,7,4′-THIF on adipogenesis in 3T3-L1 preadipocytes and elucidate the mechanisms of action involved. Methods and results: Adipogenesis was stimulated in 3T3-L1 preadipocytes. Both 6,7,4′-THIF and daidzein were treated in the presence and absence of mixture of isobutylmethylxanthine, dexamethasone, and insulin (MDI). We observed that 6,7,4′-THIF, but not daidzein, inhibited MDI-induced adipogenesis significantly at 40 and 80 μM, associated with decreased peroxisome proliferator-activated receptor-γ and C/EBP-α protein expression. 6,7,4′-THIF significantly suppressed MDI-induced lipid accumulation in the early stage of adipogenesis, attributable to a suppression of cell proliferation and the induction of cell cycle arrest. We also determined that 6,7,4′-THIF, but not daidzein, attenuated phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. 6,7,4′-THIF was found to inhibit PI3K activity via direct binding in an ATP-competitive manner. Conclusion: Our results suggest that 6,7,4′-THIF suppresses adipogenesis in 3T3-L1 preadipocytes by directly targeting PI3K. Soy isoflavones like 6,7,4′-THIF may have potential for development into novel treatment strategies for chronic obesity.